An Intronic GBF1 Variant (c.2015-19C>G) is Associated with Charcot-Marie-Tooth Disease Type 2GG by Disrupting mRNA Splicing and a comprehensive review of the literature.

Background Charcot-Marie-Tooth disease type 2GG (CMT2GG) is an autosomal dominant axonal peripheral neuropathy caused by heterozygous mutations in the GBF1 gene, primarily characterized by slowly progressive distal muscle weakness. Pathogenic variants of GBF1 associated with this disorder have been shown to be mainly located in exonic regions. This study reported a case induced by an intronic variant. Objective This study aimed to clarify the impact of the c.2015−19C > G intronic variant located in intron 16 of the GBF1 gene on pre-mRNA splicing, as well as to elucidate its potential pathogenic mechanism in CMT2GG. Methods A patient diagnosed with CMT2GG who was admitted to the Department of Neurology, Chuxiong Prefecture People's Hospital in June 2022 was retrospectively analyzed for clinical phenotype, neurophysiological findings, and imaging results. Whole-exome sequencing (WES) was performed on the proband to identify potential genetic variants, and the candidate variant was confirmed by Sanger sequencing. Reverse transcription PCR (RT-PCR) was employed to further examine the effect of the identified variant on mRNA splicing. Results The patient exhibited marked generalized muscle atrophy, and neurophysiological assessment revealed electrophysiological changes indicative of widespread neurogenic impairment. WES identified a heterozygous GBF1 variant (c.2015−19C > G), and RT-PCR analysis confirmed that this mutation affects normal mRNA splicing, resulting in nine distinct alternatively spliced transcripts. Conclusion These findings highlight the diagnostic significance of intronic variants in the GBF1 gene in CMT2GG.We believe this study will benefit researchers in the field and facilitate earlier diagnosis and treatment of CMT2GG.